2.50
Hdl Handle:
http://hdl.handle.net/10033/246131
Title:
Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy.
Authors:
Herrmann, Jennifer; Elnakady, Yasser A; Wiedmann, Romina M; Ullrich, Angelika; Rohde, Manfred ( 0000-0003-0522-3580 ) ; Kazmaier, Uli; Vollmar, Angelika M; Müller, Rolf
Abstract:
Pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy.
Affiliation:
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
Citation:
Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy. 2012, 7 (5):e37416 PLoS ONE
Journal:
PloS one
Issue Date:
2012
URI:
http://hdl.handle.net/10033/246131
DOI:
10.1371/journal.pone.0037416
PubMed ID:
22616003
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publications of Dept. Medizinische Mikrobiologie (MMIK)

Full metadata record

DC FieldValue Language
dc.contributor.authorHerrmann, Jenniferen_GB
dc.contributor.authorElnakady, Yasser Aen_GB
dc.contributor.authorWiedmann, Romina Men_GB
dc.contributor.authorUllrich, Angelikaen_GB
dc.contributor.authorRohde, Manfreden_GB
dc.contributor.authorKazmaier, Ulien_GB
dc.contributor.authorVollmar, Angelika Men_GB
dc.contributor.authorMüller, Rolfen_GB
dc.date.accessioned2012-09-27T09:11:28Zen
dc.date.available2012-09-27T09:11:28Zen
dc.date.issued2012en
dc.identifier.citationPretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy. 2012, 7 (5):e37416 PLoS ONEen_GB
dc.identifier.issn1932-6203en
dc.identifier.pmid22616003en
dc.identifier.doi10.1371/journal.pone.0037416en
dc.identifier.urihttp://hdl.handle.net/10033/246131en
dc.description.abstractPretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.subject.meshAngiogenesis Inhibitorsen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAntineoplastic Agentsen_GB
dc.subject.meshApoptosisen_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshCell Migration Inhibitionen_GB
dc.subject.meshHep G2 Cellsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMicrotubulesen_GB
dc.subject.meshMitosisen_GB
dc.subject.meshMyxococcalesen_GB
dc.subject.meshOligopeptidesen_GB
dc.subject.meshProto-Oncogene Proteins c-bcl-2en_GB
dc.subject.meshTubulinen_GB
dc.titlePretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.en_GB
dc.identifier.journalPloS oneen_GB

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